Neelima Denduluri, MD

Treating Patients With Germline BRCA-Mutated, Her2-Negative Metastatic Breast Cancer

Question

What are your thoughts about the use of poly([ADP]–ribose) polymerase (PARP) inhibitors in the adjuvant setting in BRCA-mutated, HER2-negative disease?

Answer

In the early adjuvant breast cancer setting there is a large phase 3 randomized study, OlympiA, (ClinicalTrials.gov Identifier: NCT02032823) that has now closed to accrual. We are anxiously awaiting the results to see if PARP inhibitors improve outcomes in early breast cancer as they do in BRCA-mutated metastatic disease.

In metastatic disease, use of PARP inhibitors is clearly a significant development. We have had 2 trials now, the EMBRACA trial (talazoparib; ClinicalTrials.gov Identifier: NCT01945775) and the OlympiAD trial (olaparib; ClinicalTrials.gov Identifier: NCT02000622), which have shown a progression-free survival benefit in patients with metastatic breast cancer that harbors germline mutations. When compared with the standard-of-care cytotoxic chemotherapy chosen by physicians, there was a significant progression-free survival benefit for those who received either talazoparib or olaparib. Additionally, the toxicity seems to favor the arm that received the talazoparib or olaparib compared with chemotherapy. One significant side effect of both talazoparib and olaparib is anemia, which needs careful monitoring.

We are hoping that ongoing clinical trial data will elucidate whether we can incorporate the utility of PARP inhibitors in other groups of patients with deleterious mutations that are not BRCA1/2 and in patients that harbor somatic mutations.

Question

How do you think germline mutations in the homologous recombination pathway genes could contribute to PARP inhibitor sensitivity, if at all?

Answer

Homologous recombination seems to be a predictor of response to DNA-damaging agents such as PARP inhibitors in ovarian cancer. BRCA-mutated cells have defects in the homologous recombination pathway but can also have deficiencies through other avenues. More trials are needed to see how homologous recombination can predict sensitivity to PARP in breast cancer.

Question

The addition of veliparib to carboplatin/paclitaxel in BROCADE3 (ClinicalTrials.gov Identifier: NCT02163694) significantly improved progression-free survival (PFS), but not overall survival (OS). What do you make of these seemingly discordant survival findings?

Answer

Historically, in metastatic breast cancer, we have not always seen significant benefits in overall survival. Exceptions where we have seen significant overall survival benefit is with trastuzumab and, more recently, with cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors. For a long time, studies of CDK 4/6 inhibitors also only showed a progression-free survival benefit.

While overall survival was not statistically significant with BROCADE3, the median overall survival and durable clinical benefit rate were longer in the patients that received veliparib. At 3 years, 26% of patients treated with veliparib were alive and progression free compared with 11% of patients in the placebo arm. All of these patients received doublet chemotherapy as first line — we often sequence agents. The curve separation suggests it was the maintenance veliparib that led to the PFS benefit.

Question

Extended follow-up for OlympiAD showed that OS did not differ significantly between the treatment arms studied, but that there was an OS benefit that was “suggested” by the data. What does this really mean for patients?

Answer

The same applies here as the BROCADE3 trial. The data signal that these drugs are active. We often don’t see a stunning overall survival benefit, partly due to follow-up. What we do know from OlympiAD data and EMBRACA data is that single-agent PARP inhibitors are very active in this population. We can potentially spare patients some toxicity and give single-agent PARP inhibitors alone.

Question

There was a recent warning from the US Food and Drug Administration that cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors could cause interstitial lung disease (ILD) and pneumonitis in select breast cancer patient groups. Would this warning influence your prescribing practices?

Answer

Interstitial lung disease and pneumonitis are significant toxicities associated with many antineoplastic therapies including paclitaxel and everolimus. Because of the significant benefit noted with palbociclib, ribociclib, and abemaciclib, we will continue to prescribe CDK 4/6 inhibitors, but appropriately monitor for pneumonitis as we do other toxicities.

This means that we have to watch for pneumonitis and be cognizant of it, just like with any drug. Essentially, we know that we need to recognize it, evaluate symptoms, stop the drug, and treat. Overall, CDK 4/6 inhibitors are very active and, just like with anything, we need to make sure the benefits outweigh the risk. I think in this situation, they do.

Question

A recent study presentation¹ found that the use of breast radiotherapy (as therapy and prevention) should be considered safe in the gBRCA population as it relates to secondary malignancies. What factors would likely influence the decision to administer radiotherapy?

Answer

Looking at this study it is important to remember that the data reflect a population of patients that started treatment as far back as 1991. Additionally, it was a small study with only 230 women.

What we have to remember is that radiation, even with modern techniques, does have potential long-term toxicities including cardiotoxicity. This trial is not practice changing due to relatively short follow-up. We have alternative options including better screening methods, chemoprevention, and prophylactic surgery such that contralateral radiation would not be an optimal choice, especially with the limited data.